Case Presentation: A 30-year-old woman presented to her primary care physician for two weeks of fever and flu-like symptoms attributed to an upper respiratory infection. She was prescribed prednisone, hydroxychloroquine, and doxycycline. Fevers as high as 104 degrees Fahrenheit persisted despite acetaminophen use. She developed severe abdominal pain and presented to the hospital. Exam revealed abdominal distention, epigastric tenderness, and a painful genital ulcer. Laboratory tests showed elevated aspartate transaminase (>3000 U/L), alanine transaminase (>1500 U/L) and pancytopenia (hemoglobin 9.1 g/dl, white blood cell count 2.8 cells/ul, platelet count 55 cells/ul). Imaging studies showed hepatomegaly with hepatic steatosis, moderate ascites, and mediastinal and retroperitoneal lymphadenopathy. Her genital ulcer was confirmed to be herpes simplex virus-2 (HSV-2); HSV polymerase chain reaction (PCR) from blood was qualitatively positive. She was started on intravenous acyclovir. Hematology evaluation included peripheral smear and bone marrow biopsy revealing hemophagocytosis. She was then transferred to our hospital for further evaluation and subspecialist input. Upon transfer, she was anemic but most lab parameters including liver enzymes and platelets were improving. Infectious Disease and Hematology services were consulted. Since she was improving with acyclovir in the absence of steroid therapy, it was suspected that her presentation was consistent with secondary hemophagocytic lymphohistiocytosis (HLH) due to HSV. Though quantitative HSV-2 levels were not available, Infectious Disease performed in-house cycle threshold testing that suggested HSV PCR levels were higher than anticipated for a cutaneous genital infection and more suggestive of HSV viremia. In the context of viremia, the patient’s severe hepatitis was attributed to HSV, though biopsy was deferred given improvement on acyclovir. After near resolution in the hospital, she was transitioned to valacyclovir and discharged with outpatient follow up.
Discussion: This is an unusual case of HSV hepatitis and to our knowledge, only one of two reported cases in the literature to develop severe disease from a primary genital lesion in an immunocompetent patient. Generally, primary cutaneous HSV-2 infection involves painful genital ulcers, fever, tender inguinal lymphadenopathy or may be entirely asymptomatic. Extragenital complications include neurological manifestations (e.g., aseptic meningitis, urinary retention). Disseminated HSV with hepatitis can be difficult to distinguish from other viral syndromes as mucocutaneous symptoms may be present in only 30-50% of patients. In this case, her fevers and lab criteria were typical of HLH, which is common among critically ill patients admitted to the ICU with HSV hepatitis. In fact, 16 of 33 ICU patients had hemophagocytic syndrome in a retrospective French study. Since clinical symptoms and laboratory findings can vary widely and the availability of timely HSV testing may differ across institutions, a detailed history and physical exam are essential to arrive at this diagnosis, which carries a mortality rate of ~74% regardless of treatment.
Conclusions: HSV hepatitis, while a rare cause of acute hepatitis, has a high mortality if left untreated. In the setting of febrile acute hepatitis, strong consideration should be given to HSV and possibly empiric acyclovir.